1. Field of the Invention
This invention relates to novel dihydro-3,3-diphenyl-5-(1H-pyrazol-1-ylmethyl)-2(3H)-furanone and dihydro-5-[(substituted-1H-pyrazol-1-yl)methyl]-3,3-diphenyl-2(3H)-furanon e derivatives, and their pharmaceutically acceptable lower alkyl quaternary and acid addition salts. The compounds have anticholinergic activity.
2. State of the Art
Antagonism of the action of acetylcholine at muscarinic cholinergic receptors in various tissues produces antispasmodic, antisecretory and mydriatic effects. As a result, such compounds have a broad range of therapeutic applications, notably as antispasmodics, as an adjunct in the treatment of peptic ulcer, as adjuvants in the treatment of functional disorders of the bowel or bladder, such as irritable bowel syndrome, spastic colitis, ulcerative colitis, diverticulitis and neurogenic bladder disorders (B.V. Rama Sastry in "Burger's Medicinal Chemistry", M. E. Wolff, Ed., 4th Ed., Part III, chap. 44, pg. 361).
Furanones have long been known in the realm of natural products chemistry. Pilocarpine, a 4-[1-(imidazol)methyl] 2(3H)furanone, is a naturally occurring muscarinic agonist (L. S. Goodman, A. Gilman, "The Pharmacological Basis of Therapeutics", 6th Ed., 1980, p. 87). 5-[(Diethylamino)methyl]-4,5-dihydro-3,3-diphenyl-2(3H)furanone is a furanone for which antiarrhythmic effectiveness in mammalian heart tissue, but not anticholinergic properties, has been described (A. Poland, S. African Patent 68 05, 631, Mar. 2, 1970, Eli Lilly and Co., U.S. applied Nov. 13, 1967). Another furanone, a spasmolytic that prevents contractions of isolated guinea pig ileum, is 3-[(dimethylamino)methyl]-4,5-dihydro-5,5-diphenyl-2(3H)furanone (N. Kolokouris, G. Fytas, C. Brunet, M. Luyckx, Ann, Pharm. Fr. 43(3), 1985. p. 257. The majority of presently known antimuscarinic agents are structurally similar to solanaceous alkaloids, e.g., atropine, or a diverse group of compounds including hydroxyesters, e.g., oxybutynin, amides, e.g., tropincamide, and amino alcohols, e.g., procyclidine. These groups of compounds block the effect of acetylcholine on the cholinergic receptor. The isopropyl quaternary bromide of atropine, i.e. ipratropium bromide, is particularly noteworthy for its use as a bronchodilator in the treatment of respiratory disorders, such as asthma and chronic bronchitis (G. E. Pakes, R. N. Brogden, R. C. Heel, T. M. Speight, G. S. Avery, Drugs. 20, 1980, 237-266.
The present invention provides a novel class of dihydro-3,3-diphenyl-5-(1H-pyrazol-1-ylmethyl)-2(3H)-furanone and dihydro-5-[(substituted-1H-pyrazol-1-yl)methyl]-3,3-diphenyl-2(3H)-furanon e derivatives which have anticholinergic activity